Endothelin-1 regulates cardiac sympathetic innervation in the rodent heart by controlling nerve growth factor expression

Abstract

The cardiac sympathetic nerve plays an important role in regulating cardiac function, and nerve growth factor (NGF) contributes to its development and maintenance. However, little is known about the molecular mechanisms that regulate NGF expression and sympathetic innervation of the heart. In an effort to identify regulators of NGF in cardiomyocytes, we found that endothelin-1 specifically upregulated NGF expression in primary cultured cardiomyocytes. Endothelin-1-induced NGF augmentation was mediated by the endothelin-A receptor, Gibetagamma, PKC, the Src family, EGFR, extracellular signal-regulated kinase, p38MAPK, activator protein-1, and the CCAAT/enhancer-binding protein delta element. Either conditioned medium or coculture with endothelin-1-stimulated cardiomyocytes caused NGF-mediated PC12 cell differentiation. NGF expression, cardiac sympathetic innervation, and norepinephrine concentration were specifically reduced in endothelin-1-deficient mouse hearts, but not in angiotensinogen-deficient mice. In endothelin-1-deficient mice the sympathetic stellate ganglia exhibited excess apoptosis and displayed loss of neurons at the late embryonic stage. Furthermore, cardiac-specific overexpression of NGF in endothelin-1-deficient mice overcame the reduced sympathetic innervation and loss of stellate ganglia neurons. These findings indicate that endothelin-1 regulates NGF expression in cardiomyocytes and plays a critical role in sympathetic innervation of the heart.

The Effect of Wenxin Keli on the mRNA Expression Profile of Rabbits with Myocardial Infarction

“…Moreover, downregulated genes EDN1 and ACE were both important neurohumoral factors. Inhibition of these two genes could improve cardiac function and alleviate heart failure [9, 10], consistent with the findings that WXKL group showed better EF and FS than model group. Since CTSC and TTC5 could aggravate myocardial apoptosis [11, 12], their downregulation might reduce the number of apoptotic cells as it had been verified in the Tunel staining study that WXKL group had a lower apoptosis rate than model group.…”

“…In the meantime, WXKL reduces EDN1 (endothelin 1) gene transcription, which is a potent vasoconstrictor and has a key function in sympathetic innervation of the heart [10]. Increased concentrations of EDN1 are an extremely sensitive marker of heart failure severity [18] and predict a worse prognosis.…”

Sculpting organ innervation

“…In the current study, Ieda and colleagues document that ET-1, but not several other growth factors known to act on embryonic cardiomyocytes, upregulates NGF mRNA and protein expression in myocyte cultures (4). This occurs in a Giβγ-dependent manner, consistent with the known expression of ET A by cardiac myocytes, and by established intracellular signaling pathways downstream of the ET A receptor.…”

“…How might these observations, and those of the current study (4), be used to modulate pathophysiologic responses of the heart? Following cardiac ischemic injury and reperfusion in rodents, both BDNF expression and NGF expression are dynamically regulated by myocytes and smooth muscle cells (19).…”

Sculpting organ innervation

“…Enteric neuron stem cells and differentiated progeny respond to both classes of ligand to mediate survival, differentiation, and target innervation, although sequential actions of ET-3 on gut mesenchyme to alter GDNF expression would require further evaluation. Nonetheless, these studies, together with the report by Ieda et al (4), suggest that distinct endothelin-neurotrophic factor pairing may be coordinately utilized in different target organs during embryogenesis to regulate the complex process of target innervation.…”